Conformations Consistent with Charge Migration Observed in DNA and RNA X-ray Structures

Abstract

Electron holes are known to migrate along the DNA or RNA duplexes and to localize preferentially on successive guanines. The stationary point conformations of Gua pairs that can trap or let pass these holes have been characterized by quantum chemistry calculations. Here we show their recurrent occurrence in DNA and RNA X-ray structures, often in quadruplex conformations or in interaction with proteins, ligands or metal ions. These findings give support to the biological, possibly regulatory, roles of charge migration in cell functioning.     

Studying the collective motions of the adenosine A2A receptor as a result of ligand binding using principal component analysis

Abstract

Adenosine receptors (ARs) belong to family A of GPCRs that are involved in many diseases, including cerebral and cardiac ischemic diseases, immune and inflammatory disorders, etc. Thus, they represent important therapeutic targets to treat these conditions. Computational techniques such as molecular dynamics (MD) simulations permit researchers to obtain structural information about these proteins, and principal component analysis (PCA) allows for the identification of collective motions. There are available structures for the active form (3QAK) and the inactive form (3EML) of A2AR which permit us to gain insight about their activation/inactivation mechanism. In this work, we have proposed an inverse strategy using MD simulations where the active form was coupled to the antagonist caffeine and the inactive form was coupled to adenosine agonist. Moreover, we have included four reported thermostabilizing mutations in the inactive form to study A2AR structural differences under different conditions. Some observations stand out from the PCA studies. For instance, the apo structures showed remarkable similarities, and the principal components (PCs) were rearranged in a ligand-dependent manner. Additionally, the active conformation was less stable compared to the inactive one. Some PCs inverted their direction in the presence of a ligand, and comparison of the PCs between 3EML and 3EML_ADN showed that adenosine induced major changes in the structure of A2AR. Rearrangement of PCs precedes and drives conformational changes that occur after ligand binding. Knowledge about these conformational changes provides important insights about the activity of A2AR.     

A study of the structural properties and thermal stability of human Bcl-2 by molecular dynamics simulations

The anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein interacts with several proteins that regulate the apoptotic properties of cells. In this research, we conduct several all-atom molecular dynamics (MD) simulations under high-temperature unfolding conditions, from 400 to 800?K, for 25?ns. These simulations were performed using a model of an engineered Bcl-2 human protein (Bcl-2-Δ22Σ3), which lacks 22 C-terminal residues of the transmembrane domain. The aim of this study is to gain insight into the structural behavior of Bcl-2-Δ22Σ3 by mapping the conformational movements involved in Bcl-2 stability and its biological function. To build a Bcl-2-Δ22Σ3 three-dimensional model, the protein core was built by homology modeling and the flexible loop domain (FLD, residues 33-91) by ab initio methods. Further, the entire protein model was refined by MD simulations. Afterwards, the production MD simulations showed that the FLD at 400 and 500?K has several conformations reaching into the protein core, whereas at 600?K some of the alpha-helices were lost. At 800?K, the Bcl-2 core is destabilized suggesting a possible mechanism for protein unfolding, where the alpha helices 1 and 6 were the most stable, and a reduction in the number of hydrogen bonds initially occurs. In conclusion, the structural changes and the internal protein interactions suggest that the core and the FLD are crucial components of Bcl-2 in its function of regulate ng access to the recognition sites of kinases and caspases.     

Light and Temperature Cycles as Zeitgebers of Zebrafish (Danio rerio) Circadian Activity Rhythms

Light and temperature cycles are the most important synchronizers of biological rhythms in nature. However, the relative importance of each, especially when they are not in phase, has been poorly studied. The aim of this study was to analyze the entrainment of daily locomotor activity to light and/or temperature cycles in zebrafish. Under two constant temperatures (20°C and 26°C) and 12:12 light-dark (LD) cycles, zebrafish were most active during the day (light) time and showed higher total activity at the warmer temperature, while diurnalism was higher at 20°C than at 26°C (87% and 77%, respectively). Under thermocycles (12:12 LD, 26:20°C thermophase:chryophase or TC), zebrafish daily activity synchronized to the light phase, both when the thermophase and light phase were in phase (LD/TC) or in antiphase (LD/CT). Under constant dim light (3 lux), nearly all zebrafish synchronized to thermocycles (τ=24 h), although activity rhythms (60% to 67% of activity occurred during the thermophase) were not as marked as those observed under the LD cycle. Under constant dim light of 3 lux and constant temperature (22.5°C), 4 of 6 groups of zebrafish previously entrained to thermocycles displayed free‐running rhythms (τ=22.9 to 23.6 h). These results indicate that temperature cycles alone can also entrain zebrafish locomotor activity.     

Effect of Lysine Addition on Growth of Black Iguana (Ctenosaura pectinata)

The effects of the addition of lysine to commercial feed given to captive black iguana (Ctenosaura pectinata) were evaluated in terms of growth and feed digestibility. Twenty‐eight‐day‐old black iguana with an initial weight of 5.5 ± 0.3 g were housed individually in cages measuring 45 × 45 × 45 cm. The experiment lasted 150 days. The ambient temperature ranged from 28 to 35°C with a relative humidity of 60 to 95%. Treatments consisted of the addition of different percentages of lysine to the feed (0.0, 0.1, 0.2, and 0.3%, dry matter [DM] base). There was a linear response (P < 0.01) in daily gain (68, 112, 118, and 151 mg/d) and daily intake (251, 289, 297, and 337 mg/d) for levels from 0 to 0.3%, respectively, as well in the growth in head size, snout–vent length, and total length. The digestibility of DM, neutral detergent fiber, and acid detergent fiber were reduced linearly (P < 0.01) as lysine levels increased. Intake and digestibility were negatively correlated (r = –0.74; P < 0.001). It is concluded that the addition of lysine to the black iguana diet in the first months of life is important to stimulate growth and intake. Zoo Biol 32:277–280, 2013. © 2012 Wiley Periodicals, Inc.     

Life‐History Patterns of Cuban Poeciliid Fishes (Teleostei: Cyprinodontiformes)

The following work provides basic information about the life history of 10 Cuban species of the family Poeciliidae. Adult fish stocks were captured in their natural habitat, and litters obtained from them were raised and maintained in captivity for 19 weeks. For each species, we present the mean value of newborn length (TL_o), age at sexual maturity (AM), total length at sexual maturity (TLM), as well as the patterns of postnatal growth in aquarium conditions, which were described using size–age curves and nonlinear regression equations (Richards model). There are differences in growth dynamics among species. In general, growth rates differ for both sexes in all poeciliids studied, males maturing earlier than females, who reach higher values of total length at the 19th week (TL_f). Sexual size dimorphism could be explained by the specific roles of each sex (fecundity in females and early maturity in males) while differences in growth among species could be related to their distribution patterns in the wild. The data summarized in this contribution can be useful for the conservation of these fish species. Zoo Biol 32:251–256, 2013. © 2012 Wiley Periodicals, Inc.     

Assessing changes in oral health‐related quality of life and its factors in community‐dwelling older Brazilians

doi: 10.1111/j.1741‐2358.2012.00656.x Assessing changes in oral health‐related quality of life and its factors in community‐dwelling older Brazilians Objective: To describe changes in oral health‐related quality of life and to evaluate the associations of these changes in community‐dwelling older people. Materials and methods: In this longitudinal study a representative sample of 872 older people, living in Brazil, was evaluated during 2004. The follow‐up was carried out during 2008, with 587 older persons evaluated. A questionnaire assessing socio‐demographic information, health history, oral health‐impact profile and number of natural teeth was used. Changes in oral health‐related quality of life were categorized as improvement or deterioration. Data analysis was performed using a hierarchical approach based in a conceptual framework. A hierarchal approach was carried out using Poisson regressions. Results: Older persons living in rural areas, those who reported brushing once a day or less and older persons with fewer natural teeth had an increased chance of reporting deterioration in oral health‐related quality of life. Women and participants who received a minimum wage of less than US$219.50 were more likely to report improvement in oral health‐related quality of life. Conclusion: The results of this study suggest that changes in the oral health‐related quality of life are influenced by many of the variables that were included in the conceptual framework.     

Effects of Transient and Continuous Wheel Running Activity on the Upper and Lower Limits of Entrainment to Light‐Dark Cycles in Female Hamsters

The entrainment limits to light‐dark cycles can be modified by the experimental conditions under which they are tested. Among the factors that may influence entrainment is the amount of wheel running exerted by the animal. In the present work, the effects of transitory and continuous wheel running on entrainment to light‐dark cycles were tested using a range of T cycles at the entrainment limits. Four groups of female hamsters were submitted to 1 h stepwise changes in T cycles. Two groups were exposed to T cycles of which the period was shortened at the lower limit from T22 to T18, and the other two groups were exposed to cycles that lengthened at the upper limit from T27 to T32. One of the groups at the lower limit and one at the upper limit had continuous access to a running wheel, while the others had the wheel locked, except at certain T when a lack of period control by T cycle appeared. The study demonstrates that access to running wheel widens the limits of entrainment to LD cycles. Specifically, the following observations were made: the effects of wheel running for entrainment were more evident in the groups with continuous access to wheel, as they did entrain to T19 and T32; continuous access to a wheel produced aftereffects only after T19, but not under T32; and when animals without a wheel showed relative coordination, unlocking the wheel favored entrainment in all the animals at T31, but in only 1 out 6 at T19. All of these indicate a different effect of the wheel running on the upper and lower limits of entrainment.     

Diagnosis and management of hypertension: around-the-clock ambulatory blood pressure monitoring is substantially more effective and less costly than daytime office blood pressure measurements

ABSTRACT

The cost-effectiveness of ambulatory blood pressure (BP) monitoring (ABPM) versus traditional office BP measurement (OBPM) for the diagnosis and management of hypertension has been evaluated only by few studies and based solely on the reduction of medical care expenses through avoiding treatment of isolated-office hypertension. Data from the 21963 participants in the Hygia Project, a multicenter outcomes study that incorporates into routine primary care periodic, at least yearly, 48 h ABPM evaluation, were utilized to assess the cost-effectiveness – relative to vascular pathology expenditures countrywide in Spain – of ABPM versus OBPM. The actual reported Spanish healthcare expenditure for vascular pathology in 2015 – aggregate costs of medical examinations, outpatient and inpatient care, therapeutic interventions, plus non-healthcare services (productivity losses due to morbidity/mortality and informal family/friends-provided care) – was used to compare yearly costs when diagnostic and treatment decisions for hypertension are based on the OBPM versus the ABPM-model. Our economic analysis is based on the more realistic and feasible approach of restricting ABPM solely to high-risk individuals of age ≥60 years and/or with diabetes, chronic kidney disease, and/or previous cardiovascular event, who in the Hygia Project accounted for >90% of all documented events. The projected net benefit countrywide in favor of the proposed ABPM-model is ~5294M€/year, i.e., 360.33€/year (95%CI [347.52–374.85]) per ABPM-evaluated person. This highly conservative economic analysis indicates ABPM is a much more cost-effective strategy than repeated OBPM not only for accurate diagnosis and management of true hypertension but marked reduction of expenditures on elevated BP-associated vascular pathology.     

Phylogenetic relationships of a Patagonian frog radiation,the Alsodes + Eupsophus clade (Anura: Alsodidae), with comments on the supposed paraphyly of Eupsophus

The frog clade composed of the alsodid genera Alsodes + Eupsophus is the most species‐rich of the Patagonian endemic frog clades, including nearly 31 of the slightly more than 50 species of that region. The biology of this group of frogs is poorly known, its taxonomy quite complex (particularly Alsodes), and its diversity in chromosome number striking when compared with other frogs (collectively, there are species having 2n = 22, 2n = 26, 2n = 28, 2n = 30 or 2n = 34). We present a phylogenetic analysis of this Patagonian frog clade based on mitochondrial and nuclear gene sequences. We sequenced five mitochondrial genes (cytochrome b, cytochrome oxidase I, 12S, 16S, NADH dehydrogenase subunit 1) with three intervening tRNAs, and fragments of three nuclear genes (seven in absentia homolog 1, rhodopsin exon 1, RAG‐1), for a maximum of 6510 bp for multiple specimens from 26 of the 31 species. We recovered Eupsophus as polyphyletic, with E. antartandicus, E. sylvaticus, and E. taeniatus in Batrachylidae, in accordance with most previous hypotheses. Based on this result, we transfer E. antartandicus and E. taeniatus back to Batrachyla, and E. sylvaticus to Hylorina (resurrected from the synonymy of Eupsophus), remediating the paraphyly of Eupsophus. Our results strongly corroborate the monophyly of Alsodes + Eupsophus (sensu stricto), the individual monophyly of these genera, and the monophyly of the species groups of Eupsophus. They also show the non‐monophyly of all non‐monotypic species groups of Alsodes proposed in the past. Our results expose several taxonomic problems particularly in Alsodes, and to a lesser extent in Eupsophus. This phylogenetic context suggests a rich evolutionary history of karyotypic diversification in the clade, in part corroborating previous hypotheses. In Alsodes, we predict three independent transformations of chromosome number from the plesiomorphic 2n = 26. All these, strikingly, involve increments or reductions of pairs of haploid chromosomes. Finally, the phylogenetic pattern recovered for Alsodes and Eupsophus suggests a trans‐Andean origin and diversification of the group, with multiple, independent ingressions over cis‐Andean regions.